CORE 1: COMPUTATIONAL SCIENCE Although there Is a strong methodological component to core 1, the substrate for the work contemplated here - large-scale health systems with all their quirks, biases, and heterogeneity of practice - Is by Its nature resistant to standard analytical approaches. However possible, novel methodologies for interpreting data derived from these noisy systems must provide derived data that can be documented as useful to clinical researchers, as represented by the principal investigators of our use case Driving Biology Projects. In order to tackle the challenge of developing novel analytical approaches that actually are useful for this problem, a substantial part of our. Computational Science Core (Core 1) is tool development, testing and integration of existing open source tools Into our i2b2 toolkit (aka the HIVE). Because much of our previous success in I2b2 was due to the team's determination to ensure that the tools that we generated were useable and dissemlnate-able, we believe that this next level of effort Is a worthwhile one that will further enable substratiflcation and evaluation of cohorts drawn from the clinical record. Figure 1 below illustrates the dual nature of Core 1. In the center lane is the overall goal of Core 1, namely the development of an effective and reliable Virtual Cohort Study system that builds on top of the existing i2b2 framework. To state it differently, the objective of Core 1 is to determine the extent to which one can study clinical populations in the course of their clinical care, asking the same kinds of questions asked of conventional cohort studies, using nothing more than the informational and biological by products of their health care delivery. This with an eye to rapid discovery cycles and low marginal cost with each additional study. Under this center lane, in Figure 1, is diagramed the various component tools that will be required for this effort to be successful. Many of these tools will be generated or enhanced by the methodological developments sketched above the center lane.